AU2004216554B2 - Subcutaneously-administered ganglioside-based vaccine compositions - Google Patents
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- A61K39/02—Bacterial antigens
- A61K39/095—Neisseria
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- A—HUMAN NECESSITIES
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- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
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- A—HUMAN NECESSITIES
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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Description
1 Ganglioside based Vaccine compositions for subcutaneous administration Technical field: The current invention is referred to vaccine compositions for subcutaneous administration containing gangliosides useful for the immunological 5 treatment of autoimmune diseases, infectious diseases and tumors, without any additional adjuvant. Background For a long time it is known the intention of using as immunological treatment 10 of autoimmune diseases and cancer, for instance the US-A-4965198 patent describes the use of ganglioside GM2 in the prevention and therapy of such diseases. In the filed patent EP-A-661061 and in the patent US-A-6149921, vaccine compositions are described in order to stimulate or increase the antibody response against a ganglioside which consists in an immunogen and an immunological adjuvant 15 The described immunogens are: VSSP (very small size proteoliposomes) constituted by the association of N-AcetylGM3 and N-GlycolylGM3 gangliosides from now on: (N-AcGM3) and (N-GcGM3), with the outer membrane protein complex (OMP) from Neisseria meningitidis. Such immunogens from now on will be denominated N-AcGM3NSSP and 20 N-GcGM3NSSP; they are very small size and practically invisible to the Electronic Microscope, water soluble and with increased floating capacity. For the vaccine compositions described in EP-A-661061 and US-A 6149921 the utilization of an adjuvant, such as the very well known Freund incomplete adjuvant, was required. 25 In the filed patent WO-A-02145746 vaccine compositions are described containing (A) one or more antigens with low immunogenicity; (B) VSSP with incorporated gangliosides mainly N-AcGM3NSSP and N-GcGM3NSSP; and (C) eventually one or more adjuvants. In the paper of Carr A. et al., published in Melanoma Research, 2001, Vol. 30 11, pp 219-227, the anti-tumor activity of a vaccine containing N-AcGM3 ganglioside in mice bearing melanoma B16 is described. In that article the influence of the presence of an immunological adjuvant, especially the complete Freund's adjuvant or the incomplete Freund's like adjuvant Montanide ISA 51, is also studied. The vaccines were administered intramuscularly and 2 the emerging conclusion is that mice immunized with N-AcGM3NSSP, with any of the adjuvants, Freund or Montanide ISA 51, showed IgM and IgG anti-N-AcGM3 responses at week 81h (Table 1). In contrast, the N-AcGM3NSSP vaccine without any adjuvant did not show any immunogenic response (page 223, right column). 5 Therefore the state of the art teaches that vaccines containing VSSP conjugated with gangliosides should be formulated with adjuvants, mainly the Freund's (complete or incomplete) or Montanide ISA 51. However it is very well known that when they are parentherally administered, such adjuvants, particularly the Freund's complete adjuvant, provoke some 10 inconvenient side effects such as chronic inflammation in the injection site, eventual granulomas and sterile abscess or ulcerative necrosis in tissues. Montanide ISA 51 is less aggressive but also can cause some inflammatory disorders. It would be very desirable from the point of view of their applications in the immunological treatments of autoimmune, infectious and tumoral diseases to have new 15 gangliosides vaccine compositions which are less aggressive in the injection site and that could be more easily used with less inconvenient for the patients. The discussion of documents, acts, materials, devices, articles and the like is included in this specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of 20 the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application. Throughout the description and the claims of this specification the word "comprise" and variations of the word, such as "comprising" and "comprises" is not intended to exclude other additives, components, integers or steps. 25 The authors of the present invention have discovered that the ganglioside based vaccines formulated with VSSP, when administered subcutaneously can be used without any adjuvants while there still be present the relevant immunological properties. An aspect of the present invention is to provide new vaccine compositions included in VSSP, preferably N-AcGM3/VSSP and N-GcGM3NSSP, which do not contain 30 any immunological adjuvant and are administered subcutaneously. The present invention provides a vaccine composition containing a dissolution or aqueous dispersion of one or more ganglioside included in VSSP, capable of stimulating an immune response by subcutaneous administration without any additional immunological adjuvant.
3 It is also an aspect of the present invention to provide a method for the treatment of a patient who requires a reinforcement of their immunological response that includes subcutaneous administration of the ganglioside vaccine compositions, preferably N-AcGM3NSSP and N-GcGM3NSSP, which do not contain any immunological adjuvant. 5 It is also an aspect of the present invention to provide N-AcGM3NSSP and /or N-GcGM3NSSP vaccine compositions not containing other antigenic components different from gangliosides or any other immunological adjuvants and are administered subcutaneously. 10 Detailed description of the invention The vaccine compositions aspects of the present invention consist in the dissolution or aqueous dispersion of one or more gangliosides and their inclusion into the OMP of the N. meningitidis (VSSP), capable of stimulate the immunological response by subcutaneous administration without any additional immunological adjuvant. 15 VSSP are highly stable ganglioside hydrophobic associations with the outer membrane protein complex of Neisseria meningitidis, without the necessity of covalent links. Such gangliosides-proteins systems are described in detail in patents EP-A-661061 and US-A-6149921, and also in different publications for instance, Estevez et al. Vaccine, 1999; Vol. 18(1-2): pp 190-197. In such documents the procedure for obtaining them is 20 also described. Among the gangliosides included in VSSP results a preference of the present invention the N-AcGM3 and N-GcGM3, being specially preferred the N-AcGM3. A detailed description of the immunogenicity of both conjugated gangliosides as well as their application as anticancer agents and stimulants of the 25 acquired immunity can be found in the above mentioned documents and in the review article :Bitton R. Et al., Oncology Reports (2002), Vol 9, pp 267-276, and in recent communications and scientific meetings for instance The 6 th Latin-American Congress of Immunology which took place in Havana on December 9, 2002, communication of Seurez G. et al. "Phase I clinical trial of the ganglioside cancer vaccine N-Acetil 30 GM3/VSSP/Montanide ISA 51 in advanced breast cancer patients". The vaccine compositions not containing other antigenic components than gangliosides are a preferred aspect of the invention being specially preferred those containing as unique immunogenic component N-AcGM3 (N-AcGM3NSSP) and or N- 4 GcGM3 (N-GcGM3NSSP), being specially preferred those containing only N AcGM3NSSP. The vaccine compositions aspect of the present invention are solutions or aqueous dispersion of the VSSP which can eventually contain other non-toxic, non-irritant 5 water-compatible dissolvents normally used in pharmaceuticals for parentheral use as could be polyethylenglycol. The conjugated ganglioside concentration in the solutions or aqueous dispersions is not critic and can be in the range 0,03 % - 3 % (w/v), preferably between 0,04 % and 2,5 % (w/v). The range of SC administered doses, used for the referred 10 vaccines in the present invention, is between 50 pLg and 2.4 mg, preferably between 200 pg and 2 mg. A particularly preferred characteristic of the vaccine compositions, aspect of this invention, is that they are designed to be administered subcutaneously without any additional immunological adjuvant. 15 Immunological adjuvants are frequently used in vaccine formulations Such adjuvants favored the immunogenic action in different ways: - Creating an antigen deposit in the injection site liberating or releasing the antigen in a systematic form. - Helping the antigen to reach the spleen and the lymph nodes through the formation 20 of oily micro drops easily trapped by the macrophages - Activating directly or indirectly the cells involved in the immune response. - Most known immunological adjuvants are: Freund's, complete and incomplete, Montanide ISA, Ribi adjuvants, Hunter's TiterMax, Aluminum salts, Gerbu adjuvant, QS-21, etc. 25 Surprisingly and unexpectedly the authors of the present invention have found that when gangliosidesNSSP vaccines are administered SC the adjuvants can be completely eliminated. This was, in spite of the previous state of the art, excluded almost completely for the intramuscular administration. Therefore the present invention represents undeniable advantages almost 30 all when concerns the referred inflammatory problems locally derived from the use of adjuvants. This is a method of vaccination with gangliosides simple, with efficacy and less aggressive for the patients.
5 In the following examples the comparative experimental details is included allowing to demonstrate the immunological efficacy of the vaccine composition without containing immunological adjuvants. Example 1: 5 Using the procedure described in example 3 of US-A-6149921 patent an aqueous vaccine composition was prepared (buffer Tris-HCI) containing 2,4 mg/mL of N-AcGM3NSSP. To an aliquot of such immunogen composition the same volume of Montanide ISA 51 adjuvant was added (Seppic Paris, France). At the same time to another aliquot an identical volume of buffer Tris-HCI was added. 10 Two vaccine compositions were obtained: A: Aqueous solution containing 1,2 mg/mL N-AcGM3NSSP. B: Emulsion W/O containing 1,2 mg/mL N-AcGM3NSSP. 50 C57BL/6 female mice were selected with a body weight between 18-20 g, and organized in 5 experimental groups of 10 animals each. 15 Group 1 (control) animals were inoculated intramuscularly, at days 0, 14, 28 and 42, with 0,1 mL of phosphate buffer saline (PBS). Group 2 animals were inoculated intramuscularly, at days 0, 14, 28 and 42, with 0,1 mL of vaccine composition B (120 ptg of N-AcGM3NSSP). Group 3 (control) animals were inoculated subcutaneously, at days 0, 14, 20 28 and 42, with 0, 1 mL (PBS). Group 4animals were inoculated subcutaneously, at days 0, 14, 28 and 42, with 0,1 mL of vaccine composition B (120 ptg of N-AcGM3VSSP). Group 5 animals were inoculated subcutaneously, at days 0, 14, 28 and 42, with 0,1 mL vaccine composition A (120 pg of N-AcGM3NSSP). 25 Mice in all Groups were challenged on day 63 with 5x10 3 cells of melanoma MB16F10 subcutaneously (0,2 mL). The animals were individualized since day 0 and the following parameters were determined twice a week: tumor volume, survival, and time to progression. The results obtained were the following: 30 Tumor volume: In Figure 1 tumor growth kinetic from each experimental group is shown. Mann-Whitney (two-tailed) U test was used to assess the statistical significance in the 6 paired groups of tumor volumes values from individualized animals on day 33rd after the tumor challenge. This statistical method is especially appropriate for the evaluation of this kind of experiments in which there is a natural dispersion of data related to a biologic 5 event. The p value represent the probability associated with the practical value calculated from the sample and allows to define the nearness of the Alfa value ( significance ) calculated by the stadigraph and the actual data validating the nule hypothesis (p> 0,05) 10 Results are shown in Figure 1 and Table 1 Table 1. - Effect of vaccination on tumoral volume Tumor Volume (cm 3 ) Groups Day 33 Mean Mann-Whitney U p values (Two-tailed) Group 6,53 Group 2 3,99 0,46a Group 3 6,63 Group 4 4,11 0,12b Group 5 1,89 0,01. a: p value as result of the comparison of Group 2 vs. Group 1 15 b: p value as result of the comparison of Group 4 vs. Group 3 c: p value as result of the comparison of Group 5 vs Group 3 From Figure 1 and Table 1 it can be seen that mice in Group 5, vaccinated subcutaneously with a composition object of the present invention, show a significant 20 decrease in the tumoral volume in relation to the other groups in the experiment and the corresponding controls.
7 Survival This parameter evaluates the capacity of vaccination to increase the life span of the immunized animals for a tumor as lethal as the MB16. The parameter is measured in days comparing with the survival in the non treated animals. For statistic 5 significance is used the Log-Rank test. Obtained values are shown in Figure 2 and Table 2. In Table 2 the phrase reference group X means the group which is compared with each column. 10 Table 2. Statistic of survival time according to Log-Rank test Survival (days) P p p Groups (reference (reference (reference media median Group 1) Group 3) Group 5) Group 1 35 33 - Group 2 43 36 0,06 0,26 Group 3 40 40 - - 0,002 Group 4 42 40 - 0,53 0,13 Group 5 52 53 - 0,002 These results demonstrated that mice included in Group 5, SC vaccinated with the formulation object of the present invention showed the longest survival after the inoculation of the tumor. 15 Time to Progression Time to progression is a parameter that evaluates the period that takes a tumor to be evident in each animal individually, measured since the moment of the 20 inoculation. In table 3 the results are shown: 25 8 Table 3. Statistics of the time to progression according to the Log-Rank Test. Time to progression (days) p (reference p (reference p (reference media median group) group 3) group 5) Group 19 19 - - Group 2 32 19 0,02 - 0,5 Group 3 19 19 - - 0,004 Group 4 23 19 - 0,5 0,06 Group 5 37 26 - 0,004 For mice which had not developed any tumor at the time of finishing the 5 experiment the progression was considered as 60 days. The impact in prolonging the time to progression is obviously a parameter very desired to obtain significant differences in a vaccine against cancer and according to the results observed in Table 3 the animals of Group 5, SC vaccinated with the VSSP composition object of the present invention, showed the more relevant positive results. 10 Tumor regression In Groups 4 and 5, corresponding to subcutaneous vaccination with and without adjuvant, an animal with tumor regression was observed. In the animal of Group 4 the tumor was 15 measurable at day 19th of the inoculation keeping practically without any growth until day 35 which was found negative. The mouse of Group 5 showed the presence of tumor by palpation on day 26 of inoculation and was reported as negative on day 2 9th. Overall Evaluation 20 The results of the experiments showed that the vaccine composition aspect of this invention increased the survival time and the time to progression, at the same time decreasing the tumoral growth speed in a significant way in relation to the control group treated with PBS. On the other hand the administration of a vaccine composition containing 25 the adjuvant Montanide ISA 51 only protected when administered intramuscularly showing total inefficacy when administered subcutaneously- 9 In summary the subcutaneous vaccination with the vaccine compositions aspect of this invention showed superior results in relation to the results obtained with the intramuscular way with the vaccine compositions containing an adjuvant of the Montanide type. 5 Brief description of the drawing. Figure 1 represents a graphic showing the evolution of the tumor volume in 5 Groups of animals submitted to different vaccine treatments and challenged with malignant tumors. 10 Figure 2 represents a graphic which allows appreciating the survival parameter in the 5 Groups of experimental animals.
Claims (8)
1. A vaccine composition containing a dissolution or aqueous dispersion of one or more 5 ganglioside included in VSSP, capable of stimulating an immune response by subcutaneous administration without any additional immunological adjuvant.
2. A vaccine composition according to Claim 1 in which the gangliosides included in VSSP are selected from N-AcGM3 and N-GcGM3.
3. A vaccine composition according to Claim 2 in which the ganglioside included in 10 VSSP is N-AcGM3.
4. A vaccine composition according to any one of Claims 1 to 3 in which the composition does not contain other antigens different from gangliosides.
5. A vaccine composition according to Claim 2 or 4 which contains as unique immunological components N-AcGM3/VSSP and/or N-GcGM3NSSP. 15
6. A vaccine composition according to Claim 5 which contains as unique component N AcGM3NSSP.
7. A method for the treatment of patients who requires a reinforcement of their immunological response that includes subcutaneous administration of a vaccine composition as described according to any one of Claims 1 to 6. 20
8. A vaccine composition according to Claim 1, substantially as hereinbefore described. DATED: 17 August 2005 Phillips Ormonde & Fitzpatrick Attorneys for: 25 Centro De Inmunologia Molecular
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CU20030047A CU23257A1 (en) | 2003-02-27 | 2003-02-27 | GANGLIOSID BASED VACCINE COMPOSITIONS FOR SUBCUTANEOUS ADMINISTRATION |
| CU47-2003 | 2003-02-27 | ||
| PCT/CU2004/000003 WO2004075811A2 (en) | 2003-02-27 | 2004-02-27 | Subcutaneously-administered ganglioside-based vaccine compositions |
Publications (2)
| Publication Number | Publication Date |
|---|---|
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| AU2004216554A Expired AU2004216554B2 (en) | 2003-02-27 | 2004-02-27 | Subcutaneously-administered ganglioside-based vaccine compositions |
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|---|---|
| US (1) | US8591917B2 (en) |
| EP (1) | EP1604683B1 (en) |
| JP (1) | JP4729475B2 (en) |
| KR (1) | KR100703570B1 (en) |
| CN (1) | CN100418576C (en) |
| AR (1) | AR043377A1 (en) |
| AT (1) | ATE353668T1 (en) |
| AU (1) | AU2004216554B2 (en) |
| BR (1) | BRPI0407854B1 (en) |
| CA (1) | CA2535214C (en) |
| CL (1) | CL2004000374A1 (en) |
| CR (1) | CR7965A (en) |
| CU (1) | CU23257A1 (en) |
| CY (1) | CY1106668T1 (en) |
| DE (1) | DE602004004768T2 (en) |
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| HK (1) | HK1087630A1 (en) |
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| LT (1) | LT5351B (en) |
| LV (1) | LV13400B (en) |
| MY (1) | MY139811A (en) |
| NZ (1) | NZ541952A (en) |
| PE (1) | PE20040955A1 (en) |
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| SI (1) | SI1604683T1 (en) |
| TN (1) | TNSN05209A1 (en) |
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| UA (1) | UA80859C2 (en) |
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| CU24534B1 (en) * | 2017-11-06 | 2021-07-02 | Ct Inmunologia Molecular | NANO-PARTICULATE ADJUVANTS CONTAINING SYNTHETIC VARIANTS OF GM3 GANGLIOSIDE |
| CU20170173A7 (en) | 2017-12-27 | 2019-11-04 | Ct Inmunologia Molecular | NANO-PARTICLES CONTAINING GM3 GANGLIOSIDE AS IMMUNOMODULATORS |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0661061A2 (en) * | 1993-12-29 | 1995-07-05 | Centro de Inmunologia Molecular | Vaccine composition for eliciting an immune response against N-glycolylated gangliosides and its use for cancer treatment |
| US6149921A (en) * | 1993-12-29 | 2000-11-21 | Centro De Inmunologia Molecular | Vaccine compositions for eliciting an immune response against N-acetylated gangliosides and their use for cancer treatment |
| US20020136735A1 (en) * | 2000-12-06 | 2002-09-26 | Molina Luis Enrique Fernandez | Preparations that potentiate immunogenicity in low immunogenic antigens |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4965198A (en) | 1985-12-24 | 1990-10-23 | Konica Corporation | Monoclonal antibody and method of manufacturing hybridoma producing the same |
| CA2399325A1 (en) * | 2001-08-21 | 2003-02-21 | National Research Council Of Canada | Carbohydrate-based whole cell cancer vaccines |
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2005
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2006
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2007
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0661061A2 (en) * | 1993-12-29 | 1995-07-05 | Centro de Inmunologia Molecular | Vaccine composition for eliciting an immune response against N-glycolylated gangliosides and its use for cancer treatment |
| US6149921A (en) * | 1993-12-29 | 2000-11-21 | Centro De Inmunologia Molecular | Vaccine compositions for eliciting an immune response against N-acetylated gangliosides and their use for cancer treatment |
| US20020136735A1 (en) * | 2000-12-06 | 2002-09-26 | Molina Luis Enrique Fernandez | Preparations that potentiate immunogenicity in low immunogenic antigens |
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